Patent GB-587520-A (GB)
Title: Improvements in or relating to substituted barbituric acid derivatives and salts thereof and methods of producing same
Filed: 1943-05-11
Abstract: 5.5-Disubstituted barbituric acids or salts thereof, having hypnotic and sedative unaccompanied by harmful properties, and having the general formula:  <FORM:0587520/IV/1> wherein R and R1 represent alkyl, alkenyl, cycloalkyl or cycloalkenyl groups and are like or unlike, R11 represents an alkyl group, none of the groups R, R1 and R11 contains more than 6 carbon atoms and the total number of carbon atoms in R, R1 and R11 together does not exceed 10, and X represents hydrogen, an alkali metal, the stoichiometric equivalent of an alkaline earth metal, ammonium, alkyl-ammonium, alkyl - ammonium, dialkyl - ammonium, alkylolammonium or the stoichiometric equivalent of alkylene diammonium, are obtained by condensing a disubstituted malonic ester having the general formula:  <FORM:0587520/IV/2> wherein R111 represents an alkyl group containing not more than 6 carbon atoms, with urea in an organic solvent in the presence of sodium ethylate; and the salts may be obtained by neutralising the 5.5-disubstituted barbituric acids with the corresponding bases except in the case of the alkaline earth metal salts which are obtained by reacting the alkali metal salt with an alkaline earth metal salt.  Preferred R and R11 groups are primary or secondary alkyl groups.  The preferred R1 group is a primary alkyl group. Specified R, R1 and R11 residues are: methyl, ethyl, iso propyl, allyl, n-butyl, n-amyl, isoamyl, cyclohexyl; methyl ethyl, n-propyl, isopropy isobutyl, allyl, n-hexyl; methyl, ethyl, n-propyl, isopropyl, 3-pentyl respectively in different specified combinations. In examples: (1) 5-n-butylthioethylidene-5-ethyl barbituric acid is obtained by refluxing n-butylthioethylidene ethyl malonic ester with urea in absolute alcohol containing sodium; (2) 5-n-butylthioethylidene-5-allyl barbituric acid is obtained from n-butylthioethylidene allyl malonic ester and urea as in (1); (3) 5-ethylthioisobutylidene-5-ethyl barbituric acid is obtained from ethylthioisobutylidene ethyl malonic ester and urea as in (1); (4) 5-allythioethylidene-5-isobutyl barbituric acid is obtained from allylthioethylidene isobutyl malonic ester and urea as in (1); (5) salts of the barbituric acids described above may be obtained as follows: sodium or other alkali metal: by treating the acid with sodium or other alkali metal in alcoholic solution; calcium: by treating the sodium salt with calcium chloride in alcoholic solution; ammonium, alkylamine, alkylolamine and alkylene diammonium: by treating the acid with an excess of the corresponding base and subsequently removing the excess.  Disubstituted malonic esters for use as starting materials may be obtained by the reaction between an a -halogen sulphide of the general formula R.S.CR11H.Hal. and an alkali metal derivative of a malonic ester having the general formula <FORM:0587520/IV/3> wherein the symbols have the meanings defined above and M p  represents an alkali metal in an organic solvent such as toluene or anhydrous ethanol.  In an example: diethyl-n-butylthioethylidene ethyl malonate is obtained by treating diethyl ethyl malonate with sodium in alcohol, removing the alcohol, adding toluene, and treating the solution with n-butyl-(a -chloroethyl) sulphide.  The esters used in the above examples are obtained similarly.  In the Specification as open to inspection under Sect. 91, the invention comprises the use of 5.5 substituents, wherein R and R1 are specified as hydrocarbon groups in general, but such that each contains not more than 6 and together they contain not more than 10 carbon atoms.  This subject-matter does not appear in the Specification as accepted.